DDW 2024: Bile Acid Signaling in Chronic Liver Disease: A Crosswalk with Metabolic and Autoimmune Pathways

In this session bile acid signaling in chronic liver disease by exploring the metabolic and autoimmune pathways was discussed through the findings of various studies.

Peroxisome proliferator-activated receptors (PPARs) have served as attractive therapeutic targets that could simultaneously improve steatosis, ballooning, inflammation, and fibrosis. A study examined lanifibranor, seladelpar, and elafibranor for their potency, efficacy, and selectivity against PPARα/δ/γ using assays and X-ray diffraction. The results illustrated highly variable PPARα/δ/γ activation profiles and binding modes of these PPAR ligands, defining their distinct pharmacological actions.

Another study aimed to uncover the molecular pathways responsible for reducing bile acid synthesis in hepatocytes following treatment with the selective PPARδ agonist, seladelpar. It concluded that seladelpar reduces bile acid synthesis through an FGF21-dependent mechanism, partially via c-Jun N-terminal kinase (JNK) inhibition of cholesterol 7 alpha-hydroxylase (Cyp7a1).

In chimeric PXB mice, farnesoid X receptor (FXR) agonist obeticholic acid (OCA) increased hepatic IL-31 mRNA expression and circulating human IL-31 levels. Hence suggesting a direct effect of OCA on hepatocyte IL-31 gene expression in the humanized liver murine model. 

The Primary Biliary Cholangitis (PBC) Obeticholic Acid (OCA) International Study of Efficacy (POISE) randomized, double-blind, placebo-controlled trial demonstrated that OCA reduced biomarkers associated with adverse clinical outcomes (i.e., alkaline phosphatase, bilirubin, aspartate aminotransferase, and alanine aminotransferase) in patients with PBC. The study concluded that patients treated with OCA in a trial setting had significantly greater transplant-free survival than comparable external control patients. 

The COBALT trial did not demonstrate differences in clinical outcomes between OCA and placebo; differential drop out and treatment cross-over compromised the Intent-to-treat analysis (ITT) analysis. However, the pre-specified external control as-treated analysis showed an OCA treatment effect like that demonstrated in previous outcomes studies and provides support for improved clinical outcomes with OCA. 

In a real-world study using a database, OCA treatment showed a 63% reduction in the relative risk for death, liver transplant, and hospitalization for hepatic decompensation in PBC patients with compensated liver disease. 

In a placebo-controlled trial, bezafibrate alongside ursodeoxycholic acid demonstrated a significantly higher rate of complete biochemical response in patients with primary biliary cholangitis who had an inadequate response to ursodeoxycholic acid alone, compared to placebo and ursodeoxycholic acid therapy. 

The efficacy and safety of elafibranor in primary biliary cholangitis were assessed in a multinational, phase 3, double-blind, placebo-controlled trial. It was found that treatment with elafibranor resulted in significantly greater improvements in relevant biochemical indicators of cholestasis than placebo. 

A phase 3 trial of seladelpar in primary biliary cholangitis showed that of the 193 patients who underwent randomization and treatment, 93.8% received ursodeoxycholic acid as standard-of-care background therapy. A greater percentage of the patients in the seladelpar group than in the placebo group had a biochemical response (61.7% vs. 20.0%; difference, 41.7 percentage points; 95% confidence interval [CI], 27.7 to 53.4, P<0.001).

IL-31 levels were quantified in serum samples from the ENHANCE study of patients with PBC receiving daily oral doses of placebo (n = 55), seladelpar 5 mg (n = 53) or 10 mg (n = 53) for 3 months, and for healthy volunteers (n = 55). Seladelpar decreased serum IL-31 and bile acids in patients with PBC. The reductions of IL-31 and bile acids correlated closely with each other and pruritus improvement, suggesting a mechanism to explain seladelpar’s antipruritic effects.

In the analysis of 76 children with Alagille syndrome (ALGS), all of whom were treated with maralixibat (MRX) for up to 6 years, reductions in clinically important variables were associated with improvements in event-free survival and transplant-free survival. 

GLIMMER, a randomized phase 2b dose-ranging trial of linerixibat in PBC patients with pruritus showed linerixibat effect on itch was not significantly different versus placebo in the primary intent-to-treat analysis but was associated with a significant dose-dependent reduction in itch in the per protocol population. A well-tolerated dose was identified for Phase 3 investigation for cholestatic pruritus in PBC. 

Another study demonstrated that systemic inhibition/inactivation of apical sodium- dependent bile acid transporter (ASBT) protects mice against developing severe cholestatic liver injury after bile duct ligation, by reducing bile salt pool size and increasing renal bile salt excretion. 

The effect of NGM282, an FGF19 analogue was assessed in primary sclerosing cholangitis. NGM282 potently inhibited bile acid synthesis and decreased fibrosis markers, without significantly affecting ALP levels.

Digestive Disease Week (DDW) 2024, May 18-21, 2024, Washington, D.C.